Biological and Medicinal Chemistry
The identity and status of cells is largely defined by complex communication processes that occur between and within them; dysfunction in these processes underpins much of human disease. Thus, our research is mainly focused on exploration and therapeutic manipulation of cellular signalling pathways. We design compounds for therapeutic use and as probes to investigate structure & function of signalling proteins, collaborating with molecular biologists to understand protein regulatory mechanisms.
1. Ligand Regulation of G-Protein Coupled Receptors (GPCRs)
GPCRs are a large family of transmembrane receptors that mediate signalling by numerous hormones and neurotransmitters. We develop conformationally-constrained probe compounds to investigate ligand binding properties at chemoattractant GPCRs such as FFA2 (GPR43, free fatty acid receptor) and CXCR2 (chemokine receptor).
Figure 1. Ligands for 7-TM GPCRs are used for probing cellular signalling pathways and have potential therapeutic utility.
2. Phosphodiesterase (PDE) Signalling
The activity of many GPCRs is transduced through the intracellular second messenger, cAMP. PDE enzymes downregulate cAMP, mediating its hydrolysis to AMP. Tight spatiotemporal control of [cAMP] gradients is essential for cell function and is afforded by subcellular localisation of PDEs to signalling complexes. We develop PDE4 ligands to investigate their therapeutic utility, to probe the mechanism of cross-talk between enzyme catalytic and regulatory domains, and to probe PDE4-protein binding.
Figure 2. PDE enzymes play pivotal roles in controlling cell function and are important therapeutic targets.
3. RACK1-Scaffolded Signalling
RACK1 is a 7-bladed beta-propeller protein that acts as a scaffolding hub and orchestrates formation of signalling complexes, e.g. at focal adhesions, where it interacts with cell surface integrins and IGF1R, modulating phosphorylation of focal adhesion kinase (FAK) and paxillin. As such, it regulates cell migration relevant to cancer cell metastasis. We are interested in defining RACK1 loci involved in protein associations and in developing compounds that modulate those associations.
Figure 3. cAbl kinase phosphorylates RACK1 on Tyr52 (yellow stick) and is required for IGF1R-mediated regulation of FAK.